Dopamine receptors are a family of G protein-coupled receptors (GPCRs), and can be further divided into D1-like (D1 and D5) and D2-like (D2, D3 and D4) subfamilies. In this proposal, we focus on D1 receptor, which is widely expressed in brain at high levels. Modulation of D1 activity is implicated in the treatment of many psychiatric and neurological disorders, such as schizophrenia, attention deficit hyperactivity disorder, depression, Parkinson's disease and drug addiction. One important strategy for the treatment of these diseases is to bring D1 activity back to a normal level with either agonists or antagonists, or allosteric modulators. Many D1 agonists and antagonists have been developed after decades of ligand-based efforts. However, their clinical applications have been greatly limited by their poor pharmacokinetics, lack of subtype selectivity, and common adverse effects, while the optimization based on these compounds are proven to be challenging due to their limited chemical diversity. Therefore there is a strong need for novel selective D1 receptor antagonists, agonists or allosteric modulators. The goal of this proposal is to solve the crystal structures of D1 in various activity states and identify chemically novel D1 selective agonists, antagonists and allosteric modulators from virtual screening based on these structures. The crystallization part of this proposal will build on the success of solving the structure D1-Gs protein complex internally by ConfometRx. We will aim to improve the resolution of the existing structure and solve more structures of D1 receptor bound to other agonists (dopamine or dopamine-like), antagonists or the compounds identified from virtual screening. Virtual screening efforts of this proposal will aim at identifying chemically novel compounds binding at the orthosteric site and allosteric site(s) of D1 based on the structures. We will also extend our efforts to its close homolog D5 receptor based on homology modeling, as currently there are no truly selective compounds to distinguish the function of these two subtypes. Novel lead compounds will be experimentally validated and subjected to structure-based optimization. This research will ultimately be commercialized by advancing the most promising compound through clinical trials to create a D1-specific drug with minimal side effects, likely in partnership with a large pharmaceutical company. This proposal is in response to the NIMH SBIR PA-14-172, Novel Tools for Investigating Brain-derived GPCRs in Mental Health Research (R43/R44),